M-Hemipinic acid

In a similar attempt, Decker and Eichler reduced A -methylnor-papaverinium phenolbetaine (VIII) with tin and hydrochloric acid and obtained i/i-laudanine, m.p. 112°, pierate, m.p. 162-3°, which was subsequently investigated by Spath and Epstein, who showed that on methylation it furnished dMaudanosine and that the ethyl ether on energetic oxidation yielded veratric acid (3 4-dimethoxybenzoic acid) and the methyl ethyl ether of nor-m-hemipinic acid. This clearly indicated that the free hydroxyl group was in the woquinoline nucleus, and its position was determined by the fact that on mild oxidation 7-methoxy-6-ethoxy-l-keto-2-methyl-l 2 3 4-tetrahydrowoquinoline, m.p. 95-6°, was produced, and on this basis these authors assigned formula (IX R = H R = CH3) to -laudanine. 

This with potassium hydroxide in methanol forms de-OiV-dimethylarmepavine, m.p. 86-7°, (B. HCl, m.p. 229-30°) of which the methiodide, m.p. 233-4°, on treatment with alkali decomposes into trimetHylamine and a -p-anisyl-/3-(3 4-dimethoxy- 6 - vinylphenyl) -ethylene, m.p. 79°. The latter is oxidised by permanganate in acetone to anisic and m-hemipinic acids. With ethyl sulphate and alkali, armepavine gives 0-ethylarmepavine, an oil, which permanganate oxidises to p-ethoxybenzoic acid. Armepavine is similarly oxidised to p-hydroxybenzoic acid and l-keto-6 7-dimethoxy-2-methyl-1 2 3 4-tetiahydrowoquinoline and is therefore 6 7-dimethoxy-l-p-hydroxybenzyI-2-methyI-l 2 3 4-tetrahydrowoquinoline, i.e., it is laudanosine (p. 187) with MeO. at C replaced by H and MeO at C changed to HO. ... 

It has been reported (111) that permanganate oxidation of deoxytubulo-sine (17) yielded m-hemipinic acid (124), whereas selenium dehydrogenation and zinc dust distillation of 17 and alangimarckine (18) produced harman (125). 

Application of the Hofmann and Emde reactions to tylophorinine did not lead to any useful result. Vigorous oxidation of tylophorinine gave m-hemipinic acid as the only isolable product. Mild oxidation of the methiodide yielded an imide, C19H15O5N (mp 297°), and an acid readily converted to an anhydride and yielding with diazomethane a crystalline diester, C21H20O7 (mp 160°-162°). The identity of the imide as 2,3,6-trimethoxyphenanthrene-9,10-dicarboxylimide (XIII) was established by comparison with a synthetic specimen obtained by oxidation of the dihydroisoquinoline (XIV) synthesized by the standard route from 2,3,6-trimethoxyphenanthrene-9-aldehyde. Further, the diester was shown... 

The presence of a phenanthroindolizidine ring system can be assumed on the basis of the UV- and mass-spectra. Oxidation of the alkaloid with alkaline hydrogen peroxide yielded m-hemipinic acid as the only isolable product. On the basis of its IR-spectrum and biogenetic considerations, the methoxyl groups can be assigned to the 2,3,6- or 3,6,7-positions on the phenanthroindolizidine system leading to the alternate structures XVa and XVI. It is of interest that racemic forms of both the possible structures have already been synthesized (12, 18). 

Pluviine gave m-hemipinic acid on permanganate oxidation and the red, phenolic betaine (LXXVII) under Oppenauer conditions (87). The structure of this betaine was indicated by the virtual identity of... 

Methylsalsoline, oxidized with permanganate, yields m-hemipinic acid. The position of the hydroxyl group was established by Spath, Orekhov and Kuffner (39) by synthesis, starting from isovanillin. Salsolidine was synthesized by Spath and Dengel (38). 

Permanganate oxidation of papaverine in neutral medium furnishes m-hemipinic acid (V), veratric acid (VI), papaverinic acid (a-veratroylcincho-meronic acid) (VII), and pyridine-2,3,4-tricarboxylic acid (VIII). The last-named product (VIII) may serve as evidence for the point of attachment of the nitrogen-free portion of the isoquinoline system. Dimethoxy-isoquinolines are oxidized to pyridine-3,4-dicarboxylic (cinchomeronic) acid, but papaverine yields VIII under analogous conditions, thus marking position 1 as the connecting point. 

Since fusion with alkali splits papaverine to 6,7-dimethoxyisoquinoline and 3,4-dimethoxytoluene (dimethylhomocatechol), it is likely that the latter is linked to the 1-position of the isoquinoline by way of the methyl group. The structure of the isoquinoline follows from its oxidation to m-hemipinic acid (V) and that of the dimethoxytoluene from its conversion to veratric acid (VI). 

Furthermore, corydaline, like tetrahydropalmatine, has four methoxyls, but its formula contains CH2 more, which indicates that it should be a C-methyl derivative of the latter. The final products of its oxidation by permanganate are hemipinic and m-hemipinic acid, and it is possible to isolate, along with a number of other products, the compound called coryd-aldine (LIII) (246), the structure of which has been adequately proved by... 

Constitution. The empirical formula of thalictrifoline and its ready oxidation indicates that it is a methyl homologue of either canadine or sinactine, that is, corydaline in which two of the methoxyls are replaced by a methylenedioxy group. On oxidation with iodine in methanol it is transformed into a quaternary iodide, which on reduction with zinc and hydrochloric acid yields dZ-thalictrifoline, m.p. 151°, which was also obtained by reduction of the naturally occurring dehydrothalictrifoline chloride. Complete oxidation of thalictrifoline yielded m-hemipinic acid, and therefore its structure was written as LXV. This was confirmed by demethylenation to a dihydroxy base and methylation of the latter. The new base proved to be an optically active stereoisomer of corydaline, presumably that of mesocorydaline, and on racemization by iodine oxidation and subsequent reduction was converted into mesocorydaline. 

The work of Pictet and Kramers (12) and of Danckwortt (13) indicated only that cryptopine was saturated, contained two methoxyls, one methyl on a tertiary nitrogen atom, probably a carbonyl, and also a methylene-dioxy group. The earlier observation that m-hemipinic acid could be obtained by oxidizing the alkaloid with permanganate (14) is significant only historically and serves to emphasize the difficulties that were encountered when the chemistry of the alkaloids was being born. 

Tubulosine, C29H37O3N3 (mp 261° [a]p -66°) monoacetyl (mp 186°) diacetyl (mp 151°) is a remarkable example of an alkaloid which is partly emetine and partly harmaline. Its structural determination is also an example of the powerful tools of spectral analyses in this case mass spectra for the greater part. The only chemical manipulation which gave structural information was the permanganate oxidation of the alkaloid to m-hemipinic acid. 

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